One major reason that chronic wounds do not heal is that a class of proteinases destroys the newly formed wound bed (Vaalamo et al., 1997; Weckroth et al., 1996; DiColandrea et al., 1998; Moses et al., 1996). These matrix metalloproteinases (MMPs) are normally prevented from destroying the wound bed by the action of four Tissue Inhibitors of MetalloProteinase (TIMPs1–4) that form very specific inhibitory complexes with the MMPs (e.g., Olson et al., 1997; Taylor et al., 1996; Howard et al., 1991). That is, each TIMP only inhibits a specific subset of MMPs. In chronic wounds the ratio of MMP to TIMP is high, such that most of the MMPs are uninhibited (Vaalamo et al., 1996; Saarialho-Kere, 1998). In fact, with elevated protease levels, the TIMP molecules themselves can be hydrolyzed. There is no naturally occurring TIMP molecule that singly inhibits all types of MMPs.
Hence, further approaches are needed to optimize inhibition of matrix metalloproteinases and to improve wound healing.